Atopic dermatitis (AD) is an increasingly common disease of uncertain etiology. Whereas much prior work has focused on an immunologic etiopathogenesis, recent linkage studies show that inherited mutations in a stratum corneum (SC) structural protein, filaggrin (FLG) occur in up to 30 percent of AD patients of European origin. In addition, several AD kindreds have now been described with putative gain-of-function polymorphisms in SC chymotryptic enzyme Kallikrein 7 (Klk7) and loss-of-function mutations in SPINK5, which encodes a key epidermal serine protease (SP) inhibitor, lymphoepithelial Kazal-type trypsin inhibitor (LEKTI). Together, these studies suggest that a primary abnormality in SC structure and function allows antigen access, thereby driving downstream immunologic phenomena in AD. Yet single-allele and even double-allele FLG mutations may only produce a milder, scaling disorder, ichthyosis vulgaris (IV). Our first hypothesis, therefore, is that more than one mutation may be required to transform IV into AD, and additive mutations that effect barrier function could predict convergent or divergent pathophysiological mechanisms. Yet, mutations alone may not suffice to produce AD, but superimposition of exogenous stressors, such as a decreased relative humidity (RH), repeated use of high pH surfactants, and/or sustained psychological stress (PS), could aggravate inherited structural/enzyme defects. All of these stressors are known to both disturb barrier function in normal skin, and to trigger or exacerbate AD. Their role in AD provocation will be assessed in two animal models of AD with defined, underlying SC defects. Then, we will assess the pathophysiological mechanisms leading to AD in fully genotyped humans with IV and AD, with FLG-/- plus one or more of the protease/antiprotease mutations. Further mechanistic studies will then be assessed in the animal models, including particularly the role of additive increases in pH provoking elevations in SP, with divergent, downstream pathways leading to barrier dysfunction, abnormal SC integrity, and primary cytokine release. Finally, based upon the dominant, operative pathophysiological mechanism, we will assess the potential utility of systemic and/or topical therapies that specifically target these pathomechanisms. PUBLIC HEALTH RELEVANCE. Atopic Dermatitis (AD) is an increasingly common inflammatory skin condition, predominantly affecting infants and children but its prevalence in adults is also increasing. AD not only places an enormous economic burden, but it also exacts an often-devastating toll on the quality of life of patients and families. We will be addressing the pathogenic role of inherited and acquired factors that could converge to degrade barrier function, allowing uptake of allergens leading to disease provocation. Because the current standard treatment of AD with glucocorticoids and calcineurin inhibitors is accompanied by significant side effects, alternate approaches, based upon correcting the primary barrier abnormality, could provide safer therapeutic alternatives. Because AD frequently represents the first step in the `atopic march,'which denotes the tendency to progress from initial AD in infants to include asthma and/or allergic rhinitis, therapy that corrects barrier function could also reduce the likelihood and/or severity of the `atopic march.'